In the area of PK-C inhibitors our synthetic strategy of constraining the diacylglycerol backbone into more complicated structures with specifically oriented pharmacophores has yielded stable synthetic compounds with affinities of 10 nM, already in the range of phorbol esters. Using a chiral 4,4-disubstituted heptono-1,4-lactone template we have reduced the entropy penalty associated with the poor binding of DAG. This template is currently being modified using a receptor-guided approach based on the latest crystallographic data of a phorbol ester bound to one of the zinc-finger regions of PK-Cdelta. When the rigid DAG analogues are docked at the phorbol site, two modes of binding appear theoretically possible. In order to elucidate the correct mode of binding, a series of compounds where key pharmacophores are systematically omitted have been synthesized. Preliminary results favor a particular mode of binding which will guide future molecular modifications to obtain isozyme-specific PK-C activators. A bicyclic heterocyclic ring designed with the aid of a computer algorithm (SPROUT) that fills the gaps between spatially oriented pharmacophores has recently been synthesized. The compound has a respectable Ki in the low micromolar range and it represents a lead compound for the synthesis of related analogues. The hydrolytically resistant beta-methylene analogue of thiazole-4-carboxamide adenine dinucleotide (TAD), the active metabolite of the oncolytic C-nucleoside tiazofurin, is very stable and capable of producing the desired depletion of guanine nucleotide pools even in an experimentally induced tiazofurin-resistant tumor variant. The original synthesis of beta-methylene-TAD was inconvenient and required the use of anion exchange chromatography. With the intent of working with organic soluble intermediates, and aiming at releasing the final polar product at the end of the synthesis, we have employed the Mitsunobu reaction to couple the corresponding nucleosides with a partially protected pyrophosphonate moiety. Formation of phosphonic acid esters with 2',3'-isopropylidene 6-N-benzoyladenosine and 2',3'-isopropylidene tiazofurin worked well under Mitsunobu conditions to give two different halves of the molecule, which were then assembled together.